In Psychiatry, there has been a great mystery. We know that virtually every single mental disorder identified thus far has a heritable basis. So we know that many genes are involved. At the same time, whenever we go fishing for the specific genes that are associated with any disorder, we end up with an awful lot of seaweed. Each gene explains only a fraction of the outcome, and very few genes actually replicate. This doesn't mean genes don't contribute to the manifestation of psychological traits and disorders, but it does mean we'll have to look beyond the genetic level if we want a fuller understanding of how we become who we are.

In recent years, studies keep accumulating that show the importance of gene by environment interactions. But researchers aren't just finding that the environment matters in determining whether mental illness exists. What is being discovered is far more interesting and nuanced: Some of the very same genes that under certain environmental conditions are associated with some of the lowest lows of humanity, under supportive conditions are associated with the highest highs of human flourishing.

Referred to by some scientists as the "differential susceptibility hypothesis" or journalist David Dobbs as "The Orchid Hypothesis", these findings shouldn't be understated. They are revolutionary, and suggest a serious rethinking of the role of genes in the manifestation of our psychological traits and mental "illness". Instead of all of our genes coding for particular psychological traits, it appears we have a variety of genetic mutations that are associated with sensitivity to the environment-- for better and worse.

Only a few genetic mutations have been discovered so far that demonstrate differential susceptibility effects. Most of the genes that have been discovered contribute to the production of the neurotransmitters dopamine and serotonin. Both of these biological systems contribute heavily to many aspects of humanity, including our cognitive exploration, engagement with the world, positive emotions, anxiety, depression, and mood fluctuations. So far, the evidence suggests (but is still tentative) that certain genetic variants under harsh and abusive conditions are associated with anxiety and depression, but that the very same genetic variants are associated with the lowest levels of anxiety, depression, and fear under supportive, nurturing conditions. There hasn't been too much research looking at differential susceptibility effects on other systems that involve learning and exploration, however. Enter a brand new study.

Rising superstar Rachael Grazioplene and colleagues focused on the cholinergic system-- a biological system crucially involved in neural plasticity and learning. Situations that activate the cholinergic system involve "expected uncertainty" such as going to a new country you've never been before and knowing that you're going to face things you've never faced before. This stands in contrast to "unexpected uncertainty", which occurs when your expectations are violated, such as thinking you're going to a Las Vegas family friendly Cirque Di Soleil only to realize you've actually gotten a ticket to an all-male dance revue called "Thunder from Down Under" (I have no idea where that example came from). Those sorts of experiences are more strongly related to the neurotransmitter norepinephrine.

Since the cholinergic system is most active in situations when a person can predict that learning is possible, this makes the system a prime candidate for the differential susceptibility effect. As the researchers note, unpredictable and novel environments could function as either threats or incentive rewards. When the significance of the environment is uncertain, both caution and exploration are adaptive. Therefore, traits relating to anxiety or curiosity should be influenced by cholinergic genetic variants, with developmental experiences determining whether individuals find expected uncertainty either more threatening or more promising.

To test their hypothesis, they focused on a polymorphism in the CHRNA4 gene, which builds a certain kind of neural receptor that the neurotransmitter binds to. These acetylcholine receptors are distributed throughout the brain, and are especially involved in the functioning of dopamine in the striatum. Genetic differences in the CHRNA4 gene seem to change the sensitivity of the brain's acetylcholine system because small structural changes in these receptors make acetylcholine binding more or less likely. Previous studies have shown associations between variation in the CHRNA4 gene and neuroticism as well as laboratory tests of attention and working memory.

The researchers looked at the functioning of this gene among a group of 614 children aged 8-13 enrolled in a week-long day camp. Half of the children in the day camp were selected because they had been maltreated (sexual abuse, physical abuse, neglect, emotional maltreatment), whereas the other half was carefully selected to come from the same socioeconomic status but not have experienced any maltreatment. This study provides the ideal experimental design and environmental conditions to test the differential susceptibility effect. Not only were the backgrounds of the children clearly defined, but also dramatically different from each other. Additionally, all children engaged in the same novel learning environment--an environment well suited for cholinergic functioning. What did they find?

Individuals with the T/T variation of the CHRNA4 gene who were maltreated showed higher levels of anxiety (Neuroticism) compared to those with the C allele of this gene. They appeared to be more likely to learn anxious and fearful responses to situations with higher levels of uncertainty. In contrast, those with the T/T allele who were not maltreated were low in anxiety (Neuroticism) and high in curiosity (Openness to Experience). What's more, this effect was independent of age, race, and sex. These results suggest that under normal parenting environments, the T/T allele (which is much rarer in the general population than the C allele) may be beneficial, bringing out lower levels of anxiety and increased curiosity in response to situations containing expected uncertainty.

These results are certainly exciting, but a few important caveats are in order. For one thing, the T/T genotype is very rare in the general population, which makes it all the more important for future studies to attempt to replicate these findings. Also, we're talking vanishingly small effects here. The CHRNA4 variant only explained at most 1% of the variation in neuroticism and openness to experience. So we shouldn't go around trying to predict individual people's futures based on knowledge of a single gene and a single environment.

Scientifically speaking though, this level of prediction is expected based on the fact that all of our psychological dispositions are massively polymorphic (consists of many interacting genes). Both gene-gene and gene-environment interactions must be taken into account. Indeed, recent research found that the more sensitivity ("plasticity") genes relating to the dopamine and serotonin systems adolescent males carried, the less self-regulation they displayed under unsupportive parenting conditions. In line with the differential susceptibility effect, the reverse was also found: higher levels of self-regulation were displayed by the adolescent males carrying more senstivity genes when they were reared under supportive parenting conditions.

The findings by Grazioplene and colleagues add to a growing literature on acetylcholine's role in the emergence of schizophrenia and mood disorders. As the researcher's note, these findings, while small in effect, may have clinical implications considering childhood maltreatment is a known risk factor for many psychiatric disorders. Children with the T/T genotype of CHRNA4 rs1044396 may be more likely to learn fearful responses in harsh and abusive environments, but children with the very same genotype may be more likely to display curiosity and engagement in response to uncertainty under normal or supportive conditions.

While it's profoundly difficult predicting the developmental trajectory of any single individual, this research suggests we can influence the odds that people will retreat within themselves or unleash the fundamentally human drive to explore and create.

Scott Barry Kaufman is Scientific Director of The Imagination Institute in the Positive Psychology Center at the University of Pennsylvania.